The Story of Gleevec Zavie & Shaun

[Guest guest]

I add my thanks to you Zavie - what a story! Amazing how the pieces

came together to enable us all to be together. Forever grateful, I

am. And Shaun - I love that photo of Table Mountain you have in your

profile - thats my old stomping ground. Kinda made me " homesick " a

bit. I used to climb the mountain regularly and loved sitting right

at the top where the cable car goes and look over the city..... Also

spent many happy times sailing in the bay.... those were some good

days

love and light

Annie

's mom

http://livingwithcml.blogspot.com

>

>

> Hi Zavie,

> & nbsp;

> Thanks for this info - very interesting. Shortly after I completed

my STI571 trial (Cape Town. South Africa) & nbsp;and Gleevec was

registered, I was given book by Novartis & nbsp;titled 'MAGIC CANCER

BULLET' written by & nbsp; Vasella (CEO Novartis) which

tells & nbsp;how & nbsp;gleevec was researched and finally approved & nbsp;-

interesting read.

> & nbsp;

> Regards,

> Shaun

> swatts98@... & nbsp; & nbsp;

>

>

>

> From: Zavie miller zmiller@...

> Subject: [ ] The Story of Gleevec

>

> Date: Wednesday, May 28, 2008, 4:01 AM

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> The Story of Gleevec

>

> beth Buchdunger, Ph.D.

> Juerg Zimmerman, Ph.D.

>

> In 2001, the FDA approved Gleevec®, a groundbreaking drug for

chronic myeloid leukemia (CML). What makes this drug both powerful

and gentle is that it focuses on disrupting one specific protein that

causes the cancer. This specificity allows the medicine to be strong,

while sparing other enzymes. Molecular targeting, as this technique

is known is a highly promising treatment that has been called

the " wave of the future "

> by Secretary of Health and Human Services Secretary, Tommy

. On a human level molecular targeting means vastly reduced

side effects and better chances of survival.

>

> The story of Gleevec began over four decades ago, in 1960 when

scientists at the University of Pennsylvania noticed chromosomal

abnormalities in the blood of CML patients. It wasn't until the 1980s

with the advent of genetic mapping that University of Chicago

scientists determined that the chromosomal abnormality produces a

cancer-causing kinase enzyme. With this enzyme as a target, Novartis

researchers, led by Drs. Zimmerman and Buchdunger, created and tested

400 molecules to find one that would target this enzyme without

disrupting any of the hundreds of other similar enzymes in a healthy

cell. After two years of testing, they developed the molecule that

would become Gleevec.

>

> Following another eight years of safety testing and development,

scientists were ready to try the drug in patients and found dramatic

results. Nearly every CML patient who took the drug was responding

and they reported only minimal side effects. After taking the

medicine, one patient said, " One minute I was looking at death. The

next I was looking at my whole life in front of me. " Novartis

expanded the clinical trials to make the drug available to more

patients, while the FDA put the drug on fast track to approval in

2001. The drug and the molecular targeting approach have given back

life to CML patients and brought hope to patients with other cancers.

>

> In early 1990, Dr. beth Buchdunger and Dr. Juerg Zimmerman,

both of Novartis, accepted a challenge from the leaders of the

tyrosine kinase inhibition team - Nick Lydon and Matter: Refine

the lead compound that blocks the enzyme that triggers chronic

myeloid leukemia (CML) without harming other members of the same

family, called kinases, that are needed for the body to function. Two

years and some 400 molecules later, the researchers and their

colleagues came up with the molecule that became Gleevec®, a

medicine that is helping many patients with this debilitating and

usually fatal disease and giving hope to patients with other cancers.

>

> The story of Gleevec actually began three decades earlier, in 1960,

when scientists at the University of Pennsylvania noticed that one

chromosome in the blood cells of many CML patients was shorter than

normal - it was missing a big chunk of its DNA. The stubby chromosome

was nicknamed " the Philadelphia chromosome " and marked the first time

that a chromosomal defect was linked to cancer.

>

> Scientists now had a tantalizing clue, but they didn't yet have the

tools needed to use the clue to solve the mystery of CML. Another

clue was revealed thirteen years later, when a researcher at the

University of Chicago discovered that the missing end of the short

chromosome had moved and fused with another chromosome. By the 1980s,

scientists were able to use genetic mapping to show that the two ends

of the broken chromosomes produced a cancer-causing protein, known as

Bcr-Abl. In 1986 and 1987, researchers writing in Science identified

the protein as a tyrosine kinase, a kind of enzyme that, among other

things, helps regulate cell growth and division. Bcr-Abl, the

scientists wrote, changes the cell's normal genetic instructions,

jamming the signal that tells the body to stop producing white blood

cells. As a result, while a cubic millimeter of blood from a healthy

person contains 4,000 to 10,000 white blood cells, the same volume of

a CML patient's

> blood contains 10 to 25 this number. The proliferating white blood

cells cause pain, debilitating illness, and, all too often, death.

Only three out of ten CML patients survive for even five years. Until

Gleevec, which is a daily pill, patients faced two daunting treatment

options: high-risk bone marrow transplant or daily infusions of

interferon, with side effects that have been described as " like

having a bad case of the flu every day of your life. "

>

> With the groundbreaking discovery that a single enzyme could cause

CML, medical researchers had a clear target. The search for a drug

that could block the tyrosine kinase known as Bcr-Abl was on.

>

> Ciba-Geigy, the company that later became Novartis, already had an

active program of searching for molecules that inhibited cancer

causing tyrosine kinases, targeting breast cancer and various solid

tumors.

>

> Enter Dr. Zimmermann, a medicinal chemist, and Dr. Buchdunger, a

cell biologist.

>

> " From the existing kinase program we had a molecule that showed

some activity against the enzyme but was weak, non-selective, and

toxic, "

> says Dr. Zimmermann. " The toxicity supported the hypothesis that we

shouldn't inhibit all kinases. There are hundreds of kinases in a

healthy cell, and many are important for housekeeping, such as

metabolism. We had to increase the activity of the compound and fine-

tune it so it wouldn't harm the good kinases. "

>

> It was a team effort. Dr. Zimmermann and his colleagues would

design and synthesize a molecule, and Dr. Buchdunger and her

colleagues would test the molecule against the cancer-causing enzyme.

>

> " She would tell us 'the compound is not selective' or 'it does not

penetrate the cell' and I'd have to come up will another, " recalls Dr.

> Zimmerman. " I would change the molecule. It's similar to what a

locksmith does when he has to make a key fit. You change the shape of

the key and test it. Does it fit? If not, you change it again. The

molecule has to fit into a pocket of the enzyme.... We had to do it

many times. That was frustrating, but it keeps you up and running.

For me personally, I would be bored if I only had to attempt it once.

You learn from your failures. You learn how you could do a better

job. "

>

> " You go from one step to the next, " says Dr. Buchdunger. " When you

find a compound that looks interesting in terms of specificity and

potency, then you test it for toxicity, and you hope and pray. You

keep your fingers crossed that it passes the next hurdle. "

>

> In addition to finding a molecule that was both active and

selective, the scientists had to find one that could be taken orally,

in pill form.

>

> " Oral bioavailability was a big, big hurdle, " says Dr.

Zimmermann. " For us, it was a given. We wanted a breakthrough

treatment where the patient could stay home and doesn't have to go

through all the side effects. We had to go back to the lab to improve

the uptake of the drug without losing activity and selectivity. "

>

> Novartis had been working with Dr. Druker, a haematologist

and oncologist with specific expertise in tyrosine kinases relative

to CML and then of the Dana-Faber Cancer Institute in Boston, to

profile the lead compounds identified by Buchdunger and Zimmerman.

Dr. Druker's work highlighted one compound in particular and his work

enabled the company to focus on this one compound.

>

> The compound that would become Gleevec was synthesized in 1992. For

the next several years, company and academic scientists conducted the

additional research and initial chemical and pharmaceutical

development needed to start clinical trials.

>

> " So many things need to happen before you dare give the compound to

a patient, " explains Dr. Buchdunger.

>

> The first Phase I study began in June 1998. The results of these

preliminary studies were dramatic. Nearly every CML patients who took

the drug was responding. Most patients experienced a significant

reduction in the number of white blood cells and a reduction or

disappearance in the number of cells containing the cancer-triggering

chromosome. Moreover, the patients reported only minimal side effects.

>

> Word of the drug's effectiveness spread rapidly in the CML

community - through word of mouth and Internet patient chat groups.

One of the patients who was encouraged by the trial data was Suzan

McNamara.

>

> After being diagnosed with CML in March 1998, Ms. McNamara began

her battle against the disease with a combination therapy of

hydroxyurea and interferon. She began to experience debilitating side

effects, including depression, weight loss, hair loss, and fatigue so

severe she had to stop working. She tried to enroll in a Gleevec

clinical trial, but, at that time, the supply was only adequate for

the limited number of patients needed for the Phase I Study. Knowing

what a difference the drug could make for her and others, Ms.

McNamara circulated a petition to members of the Internet support

group, collecting some 4,000 signatures. The petition asked Novartis

to move more quickly to develop the drug. In October 1999 she sent

the petition, along with a letter, to Dan Vasella, M.D., Chief

Executive Officer of Novartis. In the letter, Ms. McNamara explained

how encouraged CML patients were about the data generated by the

trials and asked that the studies be

> expanded so that more patients could participate.

>

> In fact, the company had already assigned the highest priority to

the development of Gleevec and was already expanding the larger

clinical trials to test the drug. Ms. McNamara, and thousands of

other CML patients, gained access to Gleevec through the trials. Says

Ms.

> McNamara, whose cancer is now in remission and who is studying to

be a molecular biologist: " One minute I was looking at death. The

next, I was looking at my whole life in front of me. "

>

> Positive clinical trial results prompted the U.S. Food and Drug

Administration (FDA) to grant " fast track " designation to the drug.

On May 10, 2001, only ten weeks after the company submitted a New

Drug Application, the FDA approved Gleevec for the treatment with

Philadelphia chromosome-positive CML in the blast crisis, accelerated

phase or in chronic phase after failure of interferon therapy.

> There's a disconnect between lab work and real life. When we heard

from patients, we could share the excitement. A gentleman from Texas

wrote us that he had sold his house. 'My doctor told me I was going

to die,' he wrote. Now he said his only problem is that the new owner

won't sell him back the house. And people told us that there were no

side effects.

> Before, we would just hypothesize about selectivity, but now we

know from real patients that selectivity means freedom from side

effects. For scientists, it's a dream come true: to do something in

the lab and have it help in real life. "

> *- Juerg Zimmerman, Ph.D.*

>

>

> Gleevec was immediately hailed as a major breakthrough by officials

and scientists. Secretary of Health and Human Services Tommy

called it " the wave of the future. " Dr. Harmon Eyre of the American

Cancer Society called it " a huge breakthrough…a great drug, a great

new discovery. " But for Dr. Buchdunger and Dr. Zimmermann, the most

important affirmation came from patients.

>

> " When the data started to come in, it was hard to believe, " recalls

Dr.

> Buchdunger. " But it was obvious looking at the white blood cell

counts that some patients were experiencing absolute normalization of

their blood counts. "

>

> " There's a disconnect between lab work and real life, " says Dr.

> Zimmerman. " When we heard from patients, we could share the

excitement.

> A gentleman from Texas wrote us that he had sold his house. 'My

doctor told me I was going to die,' he wrote. Now he said his only

problem is that the new owner won't sell him back the house. And

people told us that there were no side effects. Before, we would just

hypothesize about selectivity, but now we know from real patients

that selectivity means freedom from side effects. For scientists,

it's a dream come true: to do something in the lab and have it help

in real life. "

> " We have learned many lessons from this compound. The scientific

community has benefited from the idea of targeting. We have learned

useful lessons for the development of new drugs, not only for cancers

but for other diseases.. "

> *- beth Buchdunger, Ph.D.*

>

>

> Gleevec is also helping real-life patients with another kind of

cancer.

> Because of the proven activity of Gleevec against tyrosine kinases,

Demetri, M.D. of the Dana-Farber Cancer Institute, developed

and tested the hypothesis that Gleevec could be effective as a

therapy for gastrointestinal stromal tumor (GIST), a rare solid

tumor. After clinical trials, the FDA approved Gleevec for GIST on

February 1, 2002.

>

> Now, even after more than four decades of discovery, trials and

triumphs, the Gleevec story is not over. Novartis, in conjunction

with the National Cancer Institute, is conducting studies on how the

drug works, and on its long-term effect on patients. Clinical trials

are underway to study whether Gleevec works against other cancers,

including brain cancers and soft-tissue sarcomas. And scientists in

the pharmaceutical industry and in academia are conducting intensive

research to identify cancer-causing proteins in other tumors.

>

> Says Dr. Klausner, director of the National Cancer

Institute:

> " Gleevec offers proof that molecular targeting works in treating

cancer, provided that the target is correctly chosen. The challenge

now is to find these targets. "

>

> " We have learned many lessons from this compound, " says Dr.

Buchdunger, who is overseeing preclinical research on whether Gleevec

might work against other cancers. " The scientific community has

benefited from the idea of targeting. We have learned useful lessons

for the development of new drugs, not only for cancers but for other

diseases. "

>

> Zavie

>

> Zavie (age 69)

> 67 Shoreham Avenue

> Ottawa, Canada, K2G 3X3

> dxd AUG/99

> INF OCT/99 to FEB/00, CHF

> No meds FEB/00 to JAN/01

> Gleevec since MAR/27/01 (400 mg)

> CCR SEP/01. #102 in Zero Club

> 2.8 log reduction Sep/05

> 3.0 log reduction Jan/06

> 2.9 log reduction Feb/07

> 3.5 log reduction Jan/08

> 3.6 log reduction Apr/08

> e-mail: zmillersympatico (DOT) ca

> Tel: 613-726-1117

> Fax: 309-296-0807

> Cell: 613-202-0204

> ID: zaviem

> YM: zaviemiller

> Skype: Zavie

>

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